Laboratory Freeze Dryers

Freeze drying has been used in a number of applications for many years, most commonly in the food and pharmaceutical industries. There are, however, many other uses for the process including the stabilization of living materials such as microbial cultures, preservation of whole animal specimens for museum display, restoration of books and other items damaged by water, and the concentration and recovery of reaction products.

Specialized equipment is required to create the conditions conducive to the freeze drying process. This equipment is currently available and can accommodate freeze drying of materials from laboratory scale projects to industrial production.

Freeze drying involves the removal of water or other solvent from a frozen product by a process called sublimation. Sublimation occurs when a frozen liquid goes directly to the gaseous state without passing through the liquid phase. In contrast, drying at ambient temperatures from the liquid phase usually results in changes in the product, and may be suitable only for some materials. However, in freeze drying, the material does not go through the liquid phase, and it allows the preparation of a stable product that is easy to use and aesthetic in appearance.

The advantages of freeze drying are obvious. Properly freeze dried products do not need refrigeration, and can be stored at ambient temperatures. Because the cost of the specialized equipment required for freeze drying can be substantial, the process may appear to be an expensive undertaking. However, savings realized by stabilizing an otherwise unstable product at ambient temperatures, thus eliminating the need for refrigeration, more than compensate for the investment in freeze drying equipment.

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Principles of Freeze Drying

The freeze drying process consists of three stages: prefreezing, primary drying, and secondary drying.

Prefreezing: Since freeze drying is a change in state from the solid phase to the gaseous phase, material to be freeze dried must first be adequately prefrozen. The method of prefreezing and the final temperature of the frozen product can affect the ability to successfully freeze dry the material.
Rapid cooling results in small ice crystals, useful in preserving structures to be examined microscopically, but resulting in a product that is more difficult to freeze dry. Slower cooling results in larger ice crystals and less restrictive channels in the matrix during the drying process.

Products freeze in two ways, depending on the makeup of the product. The majority of products that are subjected to freeze drying consist primarily of water, the solvent, and the materials dissolved or suspended in the water, the solute. Most samples that are to be freeze dried are eutectics which are a mixture of substances that freeze at lower temperatures than the surrounding water. When the aqueous suspension is cooled, changes occur in the solute concentrations of the product matrix. And as cooling proceeds, the water is separated from the solutes as it changes to ice, creating more concentrated areas of solute. These pockets of concentrated materials have a lower freezing temperature than the water. Although a product may appear to be frozen because of all the ice present, in actuality it is not completely frozen until all of the solute in the suspension is frozen. The mixture of various concentration of solutes with the solvent constitutes the eutectic of the suspension. Only when all of the eutectic mixture is frozen is the suspension properly frozen. This is called the eutectic temperature.

It is very important in freeze drying to prefreeze the product to below the eutectic temperature before beginning the freeze drying process. Small pockets of unfrozen material remaining in the product expand and compromise the structural stability of the freeze dried product.

The second type of frozen product is a suspension that undergoes glass formation during the freezing process. Instead of forming eutectics, the entire suspension becomes increasingly viscous as the temperature is lowered. Finally the product freezes at the glass transition point forming a vitreous solid. This type of product is extremely difficult to freeze dry.

Primary drying: Several factors can affect the ability to freeze dry a frozen suspension. While these factors can be discussed independently, it must be remembered that they interact in a dynamic system, and it is this delicate balance between these factors that results in a properly freeze dried product.

After prefreezing the product, conditions must be established in which ice can be removed from the frozen product via sublimation, resulting in a dry, structurally intact product. This requires very careful control of the two parameters, temperature and pressure, involved in the freeze drying system. The rate of sublimation of ice from a frozen product depends upon the difference in vapor pressure of the product compared to the vapor pressure of the ice collector. Molecules migrate from the higher pressure sample to a lower pressure area. Since vapor pressure is related to temperature, it is necessary that the product temperature is warmer than the cold trap (ice collector) temperature. It is extremely important that the temperature at which a product is freeze dried is balanced between the temperature that maintains the frozen integrity of the product and the temperature that maximizes the vapor pressure of the product. This balance is key to optimum drying. The typical phase diagram shown in Figure 1 illustrates this point. Most products are frozen well below their eutectic or glass transition point (Point A), and then the temperature is raised to just below this critical temperature (Point B) and they are subjected to a reduced pressure. At this point the freeze drying process is started.

How Freeze Drying Works?

Refer to the phase diagram (Figure 1) and a typical sublimation cycle (Figure 2). The product is first cooled to below its eutectic temperature (Point A). The collector is cooled to a temperature approximately 20° C cooler than the product temperature, generally around -50 to -80° C. The product should be freeze dried at a temperature slightly lower than its eutectic or collapse temperature (Point B) since the colder the product, the longer the time required to complete primary drying, and the colder the collector temperature required to adequately freeze dry the product.

After the product is adequately frozen and the collector temperature achieved, the system is evacuated using a vacuum pump (Point C). At this point, primary drying of the product begins and continues until the entire frozen matrix appears dry. Heat input to the product may be achieved by several means such as increasing the shelf temperature in the case of tray drying, or using a liquid bath for manifold drying. While the collector and vacuum pump create the conditions for allowing sublimation to occur, heat input is really the driving force behind the whole process.

Heat input to the sample can be enhanced by controlling the pressure in the system at some level above the ultimate capability of the vacuum pump. Some freeze dryers incorporate vacuum control systems that automatically regulate the pressure to the preset level. This allows additional gas molecules to reside in the system thereby improving the conduction of heat to the sample. This improves the sublimation rate, reducing process time and associated energy costs. Care must be taken to prevent the pressure within the system from exceeding the ice vapor pressure of the product or melting of the sample may occur.

Freeze Drying Methods

Three methods of freeze drying are commonly used:(1) manifold drying, (2) batch drying, and (3) bulk drying. Each method has a specific purpose, and the method used depends on the product and the final configuration desired.

Manifold Method. In the manifold method, flasks, ampules or vials are individually attached to the ports of a manifold or drying chamber. The product is either frozen in a freezer, by direct submersion in a low temperature bath, or by shell freezing, depending on the nature of the product and the volume to be freeze dried. The prefrozen product is quickly attached to the drying chamber or manifold to prevent warming. The vacuum must be created in the product container quickly, and the operator relies on evaporative cooling to maintain the low temperature of the product. This procedure can only be used for relatively small volumes and products with high eutectic and collapse temperatures.

Manifold drying has several advantages over batch tray drying. Since the vessels are attached to the manifold individually, each vial or flask has a direct path to the collector. This removes some of the competition for molecular space created in a batch system, and is most ideally realized in a cylindrical drying chamber where the distance from the collector to each product vessel is the same. In a “tee” manifold, the water molecules leaving the product in vessels farthest from the collector experience some traffic congestion as they travel past the ports of other vessels.

Heat input can be affected by simply exposing the vessels to ambient temperature or via a circulating bath. For some products, where precise temperature control is required, manifold drying may not be suitable.

Several vessels can be accommodated on a manifold system allowing drying of different products at the same time, in different sized vessels, with a variety of closure systems. Since the products and their volumes may differ, each vessel can be removed from the manifold separately as its drying is completed. The close proximity to the collector also creates an environment that maximizes drying efficiency.

Batch Method. In batch drying, large numbers of similar sized vessels containing like products are placed together in a tray dryer. The product is usually prefrozen on the shelf of the tray dryer. Precise control of the product temperature and the amount of heat applied to the product during drying can be maintained. Generally all vials in the batch are treated alike during the drying process, although some variation in the system can occur. Slight differences in heat input from the shelf can be experienced in different areas. Vials located in the front portion of the shelf may be radiantly heated through the clear door. These slight variations can result in small differences in residual moisture.

Batch drying allows closure of all vials in a lot at the same time, under the same atmospheric conditions. The vials can be stoppered in a vacuum, or after backfilling with inert gas. Stoppering of all vials at the same time ensures a uniform environment in each vial and uniform product stability during storage. Batch drying is used to prepare large numbers of ampules or vials of one product and is commonly used in the pharmaceutical industry.

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